1-(di-n-butylaminoalkylamino)-4-methylthiaxanthones and synthesis thereof



Patented Sept. 29, 1953 UNITED G-FF'I'GE METHYLTHIAXAN THESIS THEREOF sydney ch rgA ha N- assiaaor asterlia u New. PI a. arr t? Je Qt;

Delaware N MQWM:

: tiia l 197,111 1 pplication-Nqvemberzz;1950,

2 c aim (01. 260-328) This inventionv relates to 1-.(dirn -buty1amino alkylamino) -4-methylthiaxanthone -.andtto their method of preparation. In.partioular it relates to such thiaxanthones having the structural formula lower alkylene radical, designated hereinabove as X, has preferably from 2-4 carbon atoms, in-

elusive. X thus comprehendssuch radicals as o cHz+, cr c 3) CH(CH3 carers acia- 5 and the like.

My compounds are, prepared by heating, preferably in refluxing pyridine at atmospheric pressure, a di-n-butylaminoalkylamine having the formula, (CH3CH2CH2CH2) 2N-:X-N H2, with a l-halo-4-methylthiaxanthone having the formula 0 h l en wh halogen mea 1. mm b qm y qdp and l n h X a R hav th meen a s d s nated hereinabove. The intermediate1:11am-4- g up. a ow a k l radi a r a awe @lKQKY lie ical are prepared by cyclizing a 2-(2-methyl-5- 2. halo-phenylmercapto) -4-R -be n zoic acid. These m ermediate. ri2r ethy x- 5 W nt-11m? canto) r'iirfirbenzq c, aciqawhi h are im a ed by heating a metal salt of a 2 -halo-4-slubstituted benzoi sidiwith a metal salt of. a 2-methyl-5- halethiopnenol inthen esen e O a o er 0 1,- lyst, are described and claimed inmy copending a ation. erial iumher 7 7 l d N embe -:2 .wfll o baadone The. ntermedi t .-Qh IQ -m t h e r .thone (whereB, is 1:1) was obtained, mixed with ac d suliuric acid, I alsoprepared this mixtur i isomer c qhlqr :methvlth asaa on s b substituting dithiosaiicychc ac d ijortn osancycl c acid in the condensation with para-chlorotoluene,

a specific adaptation ofja. general procedure first discovered by Davies and, SmileslJ. Chem. Soc. 97, 1290 (1909)]. This mixture of isomeric thiaxanthones can be used satisfactorily inthe condensation with a di-n-butylaminoalkylamme since only the 1-ch1oro-4-methyl isomer reacts with the diamine'.

lllustrative'of my. invention are the preparations of 1-(2 (ii -..n butylaminoethylamino) '-4- methyl 7 iodothiaxanthone, IHZ-di-n-butylaminoethylammo) -,.4 methyl 7 ethyltni'a xanthone and 1-.(21di-n-butylaminoethylammo 4-methyl-7-isopropo5iythiaxanthone in the form of their hydrohalideaddition' salts byreactmg 2-di-n-butylaminoethylamine with l-chloro-4- methyl-57-iodothiaxanthorie, l-bromo--methylfl-ethylthiaxanthone and '1-.iOd0-4-.m8Lhyl-7-lS0- propoxythiaxanthone, respectively. Reactionof 2- (di-n-butylamino)ethylamine with the above described mixture of 1chloro-4-methylthiaX'anthone and I-methyl-f4-chlorothiaXanthone' results, in the formation of 1-(2-di-n butylaminoethyla'mino)a4;methylthiaxanthone in the form of its hydrochloride addition salt.

I My 1 (2 'di 'n butylaminoalkylamino 4-.methylthiaxanthones are therapeutically active when administered orally whether employed as the free bases or. as their salts with relatively :non-toxic organic or inorganic acids, alth h most cases the salt form is more convenient to employ. Ifound it convenient to isolate my compounds as the hydrohalides, especially the hydrochlorides. However, other acid addition salts are within the scope of my-inventiomsuch salts including the phosphates, sulfates, "bitrates, ethanesulfonates, tartrates, succinates, acetates, benzoates, mandelates', "oleates, and the like.

Specific embodiments of my invention are further illustrated in the following examples:

EXAMPLE 1 A. 1-ehloro-4,7-dimethylthiaxcnthone A mixture of g. of 2-(2-methyl-5-chlorophenylmercapto) 4 methylbenzoic acid and 100 g. of concentrated sulfuric acid was heated with stirring on a steam bath for ninety minutes. The reaction mixture was cooled, poured into water and the resulting aqueous mixture filtered. The yellow solid was suspended in dilute ammonia and heated to boiling. After ten minutes the solid was filtered, washed with water and then with acetone, and dried. There was thus obtained 8.5 g. of 1-chloro-4,7-dimethylthiaxanthone, M. P. 147.8-148.8 C. (cor.) when recrystallized from acetic acid-water.

AnaZ.-Calcd. for CH11C1OS; C, 65.56; H, 4.04. Found: C, 65.47; H, 4.35.

Other 1-halo-4-methyl-7-alkylthiaxanthones can be obtained according to the foregoing procedure by using other 2-(2-methyl-5-halophenylmercapto)-4-all ylbenzoic acids in place of 2-(2- methyl 5 chlorophenylmercapto) 4 methylbenzoic acid. Thus, using 2-(2-methy1-5-bromophenylmercapto) 4 ethylbenzoic acid, 2 (2- methyl 5 iodophenylmercapto) 4 isopropylbenzoic acid, 2-(2-methyl-5-chlorophenylmercapto)-4-n-butylbenzoic acid and 2-(2-methyl- 5 chlorophenylmercapto) 4 isobutylbenzoic acid, there is obtained, respectively, 1-bromo-4- methyl-7-ethylthiaxanthone, 1-iodo-4-methyl-7- isopropylthiaxanthone, 1-chloro-4-methyl-7-n butylthiaxanthone and 1-chloro-4-methyl-7-iso.- butylthiaxanthone.

B. 1-(2-di n butylaminoethylamino) 4,7 dimethylthiazranthone hydrochloride A mixture of 6.0 g. of 1-ch1oro4,7-dimethylthiaxanthone, 5.0 g. of Z-di-n-butylaminoethylamine and 5.0 g. of pyridine was refluxed for eighteen hours at atmospheric pressure. The solution was cooled to 80 0., treated with about ml. of absolute ethanol, and the resulting solution was boiled and then filtered. To the hot filtrate there was added an excess of 25% ethanolic hydrogen chloride. On cooling, the desired hydrochloride separated. It was filtered, washed with cold ethanol and dried. This product, 1- (2-di-n-butylaminoethylamino) 4,7 dimethylthiaxanthone hydrochloride, melted at 153.5- 154.7 C. (cor.) when recrystallized from acetone, with charcoaling.

AnaZ.Calcd. for C25H34N2OS.HC1: N, 6.27; S, 7.17. Found: N, 6.19; S, 7.46.

Other 1-(2-di n butylaminoethylamino) 4- methy1-7-alkylthiaxanthones can be prepared following the directions given above, but using other 1-halo-4-methyl-7-alkylthiaxanthones in place of 1 chloro 4,7 dimethylthiaxanthone. Thus, using l-bromo-4-methyl-7-ethylthiaxanthone, 1-iodo-4-methyl-7-isopropylthiaxanthone, 1-chloro-4-methyl-'7n-butylthiaxanthone and 1- chloro-4-methyl-7-isobutylthiaxanthone, there is obtained l-(2-di-n butylaminoethylamino) 4- methyl 7 ethylthiaxanthone hydrobromide, 1- (2-di-n-butylaminoethylamino) 4 methyl 7- isopropylthiaxanthcne hydroiodide, 1-(2-di-nbutylaminoethylamino)-4-methyl-7 n butylthiaxanthone hydrochloride and 1-(2-di-n-butylaminoethylamino) -4-methyl-7 isobutylthiaxanthone hydrochloride, respectively.

4 EXAMPLE 2 A. 1,7-dichloro-4-methylthiaranthone This preparation was carried out according to the procedure described hereinabove for Example 1A, but using 4.0 g. of 2-(2-methyl-5-chlorophenylmercapto) -4-chlorobenzoic acid and 40 g. of sulfuric acid. There was thus obtained 3.5 g. of 1,7-dichloro -4 methylthiaxanthone, M. P. 196-197 C. (cor.) when recrystallized from acetic acid.

Anal.Calcd. for C14HBC12OSZ C, 57.1; H, 2.71. Found: C, 57.5; H, 2.94.

Other 1,7-dihalo-4-methylthiaxanthones can be prepared according to the above procedure by substituting the appropriate 2-(2-methyl-5-halophenylmercapto)-4-halobenzoic acid for 2-(2- methyl-5-chlorophenylmercapto) 4 chlorobenzoic acid. Thus, using 2-(2-methyl-5-bromophenylmercapto)-4-bromobenzoic acid, 2-(2- methyl-5-iodophenylmercapto) 4 iodobenzoic acid, 2 (2-methyl-5-chlorophenylmercapto 4 bromobenzoic acid and 2-(2-methyl-5-chlorophenylmercapto) -4-iod0benzoic acid, there is obtained 1,7-dibromo-4-methylthiaxanthone, 1,7- diiodo-4-methylthiaxanthone, l-chloro-4-methyl -7-bromothiaxanthone and 1-chloro-4-methyl- 7 -iodothiaxanthone, respectively.

B. 1 (2-di-n-butylaminoethylamino) -4-methyl- 7-chlorothiamanthone hydrochloride A mixture of 3.5 g. of 1,7-dichloro-4-methylthiaxanthone, 3.0 g. of Z-di-n-butylaminoethylamine and 3 g. of pyridine was refluxed for eighteen hours. The solution was cooled, treated with a 50% aqueous potassium hydroxide solution, and the resulting alkaline solution steamdistilled. The residue was cooled and taken up in chloroform. The chloroform solution was dried and the chloroform was removed by distillation under reduced pressure. The oil that remained was dissolved in dry ether, the ether solution filtered and the filtrate treated with ethanolic hydrogen chloride, whereupon there separated the product, l-(z-di-n-butylaminoethylamino) -4-methyl-7-chlorothiaxanthone hydrochloride, which melted at 164.4-l65.6 C. (cor.) when recrystallized from ethanol-ether.

AnaZ.--Calcd. for C24H31C1N2OS. HCl: N, 5.99. Found: N, 5.72.

Other 1-(2-di -n butylaminoethylamino)-4- methyl-7-halothiaxanthones can be prepared according to the procedure given above, but using other 1,7-dihalo-4-methylthiaxanthones in place of 1,7 dichloro 4 methylthiaxanthone. Thus, using 1,7-dibromo-4-methylthiaxanthone or 1- chloro-4-methyl-7-bromothiaxanthone, there is obtained 1 (2 di-n-butylaminoethylamino) -4- methyl-7-bromothiaxanthone in the form of its hydrobromide or hydrochloride addition salt, respectively. Using 1,7 diiodo-4-methylthiaxanthone or 1-ch1oro-4-methyl-7iodothiaxanthone, there is obtained 1-(2-dim-butylaminoethylamino) -4-methyl-7-iodothiaxanthone in the form of its hydroiodide or hydrochloride addition salt, respectively.

EXAMPLE 3 A. 1 -chloro-4-methyZ-7-methoxythiazranthone The preparation of this compound was carried out following the procedure described hereinabove in Example 1A, but using 16.0 g. of 2-(2-methyl- 5-chlorophenylmercapto) -4-methoxybenzoic acid and g. of sulfuric acid, and a heating period of thirty minutes. There was obtained 9.7 g. of 1-chloro-4-methyl-7-methoxythiaxanthone, M. P.

ism-190.1 c. (cor.) when frecry'stallizedlfrom .acetic acid.

B. 1-(2-di-n-butylaminoethilldmino)-4-methyl- 7 -methoazythia:mnthone hydrochloride This compound can be prepared following the procedure given hereinabove for Exam'ple 1B, but using 1-chloro-4-methyl-7-methoxythiaxanthone' in place of 1 chloroifl-dimethylthiaxan thone. The product thus obtained-is 1-(2-di-nbutylaminoethylamino) 4 methyl -7'- methoxythiaxanthone hydrochloride.

Other 1 (2-di-n-butylaminoethylamino) -4- methyl-7-alkoxythiaxanthones: can be prepared according to the procedure given above, but using other l-halol-methyl 'l-alkoxythiaxanthones in place of l-chloro-i-methyl 'l -methoxythiaxanthone. Thus, using 1-bromo-4-methyl-7-ethoxythiaxanthone, 1-iodo-4-methyl-7-n-propoxythiaxanthone, l-chloro-4-methyl -'7- isobutoxythiaxanthone l chloro-4 methyl 7 n -butoxytliialxanthone, there is obtained 1-(2-di-n-butylaminoethylamino) -4-methyl-'l-ethoxythiaxanthone hydrobromide, 1 (2-di-n-butylaminoethylamino) l-methyl-l-n-propoxythiaxanthonehydroiodide, 1 (2 di-n-butylaminoethylamino) -4-methyl7- isobutoxythiaxanthone hydrochloride and 1-(2- di n-butylaminoethylamino) -4-methyl-7-n-butoxythiaxanthone hydrochloride, respectively.

EXAMPLE 4 A. 1-chloro-4-methylthiamanthone The following preparation yields a mixture of the desired 1-chloro-4-methylthiaxanthone and its isomer, 1-methyl-4-chlorothiaxanthone, said mixture being satisfactory for use in the condensation reaction described below in Example 43.

A mixture of 150 ml. of p-chlorotoluene and 1500 m1. of sulfuric acid was stirred vigorously at -30" C. as g. of pure thiosalicylic acid was added. Th mixture turned dark red, sulfur dioxide was evolved and the temperature rose about ten to fifteen degrees. Stirring was continued for about sixteen hours at room temperature then the mixture was held at 60 C. for two hours. The solution was poured into an ice-water mixture and filtered. The yellow solid was suspended in dilute ammonia and steam was passed into the suspension for thirty minutes to remove any unreacted p-chlorotoluene. Then the solid was collected on a filter and washed successively with water, alcohol and acetone. On drying there was obtained 83 g. (81%) of the thiaxanthone mixture suitable for use in the condensation with the diamine. It melted at 142-145" C. (uncor.). Upon crystallization from acetic acid the melting point was raisedsliglitly-td14514790. "Th' lbss on crystallization 'wasabout 20 In another experiment 159 g. oficrude" dithiosalicylic acidwas condensed with"750'ml.' of'pchlorotoluene in' the presence of 1250 ml. of sulfuric acid. .The temperature rise upon the addition of'th 'dithio acid was about five degrees. r At the end of the reactionthemixture'waspour'ed into ice-water and the suspension steam distilled to remove excessp-chlorotoluene. "Thesolidwas collected and treated asabove. Th'ere was ob- .tained 175 g. (65%) of the mixture of 1'-chloro potassium hydroxide solution. The 'alkalinemixture was steam-distilled torem'ovethe volatile bases. The residue was cooled and the supernatant liquid was carefully decanted. The-"residue was boiled with-500.ml.-of- ;10%- aqueous acetic acid and filtered. The insoluble residue was boiled again with two 100"ml.'= portions of 10% aqueous acetic-acid,f*the solid -being: filtered after each extraction. Theac'id-filtrates were combined and made alkaline. IThe precipitated product was collectedin"chloroform. After-drying, the solutionwas'concentrated in vacuo and the residue dissolved in dryether. The ether solution was filtered'and the filtrate was treated with a slight excess of 'ethanolic hydroge'ir'chloride. The solid which deposited was' filtered rand dried. Wt. 11.0 g. This product, l-(2-di-ni butylaminoethylamino) 4em'eth'ylthiaxanthone hydrochloride, melted at: -16631-1671? C. (cor.'.) 'when crystallized'from acetone and dried at 75 C'flfor at least twenty-four hours.

AnaZ.Calcd. for C24H32N2OS.HC1: N, 6.47; S, 7.4 1. Found: N, 6.25; S, 7.52.

The above hydrochloride salt was sparingly soluble in cold water but readily soluble in hot water. The pure hydrochloride could be recrystallized from water. The corresponding ethanesulfonate was prepared from the hydrochloride as follows: A sample of the hydroclorid was dissolved in warm water and the solution was made alkaline with sodium carbonate solution. The liberated 1-(2-di-n-butylaminoethylamino)-4-methylthiaxanthone was taken up in chloroform. The chloroform was concentrated to dryness under reduced pressure and the residue dissolved in ether. To the ether solution was added a slight excess of ethanesulionie acid whereupon there separated a gum which solidified on scratching. This salt, 1-(2-di-nbutylaminoethylamino) 4 methylthiaxanthone ethanesulfonate, was very soluble in cold water and melted at 142-144.4 C. (cor.) when recrystallized from acetone-ether.

AnaI.--Calcd. for C24H32N2OS.C2H5SO3H2 N, 5.53; S, 12.66. Found: N, 5.60; S, 12.90.

EXAMPLE 5 A. Di-n-butylaminoacetone A modification of the method of Breslow et al. [JACS 68, (1946)] was used in this preparation. A solution of 181 g. of di-n-butylamine in B. 1-di-n-butyZamino-Z-propylamine A solution of 75 g. of di-n-butylaminoacetone in 350 ml. of 15% methanolic ammonia was treated with Raney nickel catalyst and reduced at 640 p. s. i. at 75 C. in five hours. The catalyst was filtered off and the filtrate distilled first at atmospheric pressure and then under reduced pressure. The product, 1-di-n-butylamino-2-propy1- amine, which boiled at 59 C. at 0.9 mm., Weighed 55 g. (73%).

AnaZ.-Ca1cd. for C11H26N2t N, 15.03. Found: N, 14.81.

C. 1-1(di-n-butyZamino-2-propylamino) -4- methylthiaxanthone hydrochloride This preparation was carried out according to the procedure described hereinabove in Example 2B, but using 20 g. of a mixture of l-chloro-4- methylthiaxanthone and its 1-methyl-4-chloro isomer, 12 g. of 1-di-n-butylamino-2-propyl- 5.

amine and 10 g. of pyridine. The product, 1-(1- di n butylamino 2 propylamino) 4 methylthiaxanthone hydrochloride, melted at 192-193.5 C. (cor.), when recrystallized from acetone-ether.

AnaZ.Calcd. for C25Ha4N2OSl-IC1: N, 6.27; S, 7.17. Found: N, 5.97; S, 6.82.

Other 1- (1-din-buty1amin0-2-propylamin0) 4-methylthiaxanthones can be prepared according to the above procedure using other 1-halo-4- methylthiaxanthones in place of the mixture of 1-chloro-4-methylthiaxanthone and its l-methyl- 4-chloro isomer. Thus, l-(l-di-n-butylamino-Z- propylamino) 4 methyl 7 chlorothiaxanthone hydrochloride, l-(l-di-n-butylamino- 2-propylamino) 4,7 dimethylthiaxanthone hydrochloride and 1-(l-di-n-butylamino-2-propylamino) -4-methyl-7-methoxythiaxanthone hydrochloride are formed using 1,7-dichloro-4-methylthiaxanthone, 1 chloro 4,7 dimethylthiaxanthone and 1 chloro 4 methyl 7 methoxythiaxanthone, respectively.

I claim:

1. 1 (2 di n butylaminoethylamino) 4 methylthiaxanthone having the formula which comprises heating l-chloro-l-methylthiaxanthone with 2-di-n-butylaminoethylamine.

SYDNEY ARCHER.

References Cited in the file of this patent Mauss, Chem. Berichte 81, pp. 19 -31 (1948).

Fiat Review of German Science, Chemotherapy, Office of Military Government for Germany, 1948, pp. 283-288. 

1. 1 -(2-DI-N-BUTYLAMINOETHYLAMINO) -4METHYLTHIAXANTHONE HAVING THE FORMULA 